Deadline: 27-08-2012
Leiden University
Leiden University
Job description
The project is funded
by a Dutch Cancer Foundation (KWF) and is entitled ‘Novel Protein
Kinases Targets In IGF-1 and EGF Receptor - Mediated Drug Resistant
Breast Cancer’.
Treatment of breast cancer has improved with the introduction of anti-estrogen therapy. Yet a large percentage (>40%) of tamoxifen treated breast cancers eventually become resistant to tamoxifen, and also resistance to other anti-estrogens has been reported. Resistance to anti-estrogens has been linked to increased expression and/or activation of various receptor tyrosine kinases (RTKs) such as EGFR, IGF-1R and HER2. This may lead to downstream phosphorylation of the estrogen receptor and insensitivity to the antagonistic action of anti-estrogens.
We have recently established relevant models for anti-estrogen resistant breast cancer by ectopically expressing the human EGFR and IGF-1R in human MCF7 breast cancer cells. When stimulated with EGF or IGF1 respectively, these cells are almost completely resistant to inhibition of estradiol-induced cell proliferation by tamoxifen and fulvestrant. Using genome-wide protein kinase and phosphatase siRNA-based screening we identified >35 kinases and phosphatases in MCF7/IGF-1R cells that reversed the IGF1-induced tamoxifen resistance. These candidates may represent potentially novel drug targets for anti-estrogen resistant breast cancer. The goals of this project are to characterize these novel drug targets with respect to their role in tamoxifen resistance, breast cancer cell proliferation and survival in 3D models in vitro, and to validate the role of a selected number of these drug target candidates in control of cell proliferation, tamoxifen resistance, and tumor progression in vivo, in xenograft tumor models in mice.
Treatment of breast cancer has improved with the introduction of anti-estrogen therapy. Yet a large percentage (>40%) of tamoxifen treated breast cancers eventually become resistant to tamoxifen, and also resistance to other anti-estrogens has been reported. Resistance to anti-estrogens has been linked to increased expression and/or activation of various receptor tyrosine kinases (RTKs) such as EGFR, IGF-1R and HER2. This may lead to downstream phosphorylation of the estrogen receptor and insensitivity to the antagonistic action of anti-estrogens.
We have recently established relevant models for anti-estrogen resistant breast cancer by ectopically expressing the human EGFR and IGF-1R in human MCF7 breast cancer cells. When stimulated with EGF or IGF1 respectively, these cells are almost completely resistant to inhibition of estradiol-induced cell proliferation by tamoxifen and fulvestrant. Using genome-wide protein kinase and phosphatase siRNA-based screening we identified >35 kinases and phosphatases in MCF7/IGF-1R cells that reversed the IGF1-induced tamoxifen resistance. These candidates may represent potentially novel drug targets for anti-estrogen resistant breast cancer. The goals of this project are to characterize these novel drug targets with respect to their role in tamoxifen resistance, breast cancer cell proliferation and survival in 3D models in vitro, and to validate the role of a selected number of these drug target candidates in control of cell proliferation, tamoxifen resistance, and tumor progression in vivo, in xenograft tumor models in mice.
Requirements
We
seek a talented and highly motivated candidate with proven experience
in cell and molecular biology, cell signalling and light microscopy. The
candidate should have a MSc degree in (Medical) Biology, Life Science
Technology, Bio-Pharmaceutical Sciences or any other closely related
discipline. Experience or affinity with image analysis is recommended.
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